DM is a dominantly-inherited, multisystemic disease with a consistent constellation of seemingly unrelated and rare clinical features including: myotonia, muscular dystrophy, cardiac conduction defects, posterior iridescent cataracts, and endocrine disorders (Harper, Myotonic Dystrophy, W. B. Saunders, London, ed. 2, 1989)). DM was first described nearly 100 years ago, but the existence of more than one genetic cause was only recognized after genetic testing became available for myotonic dystrophy type 1 (DM1) (Thornton et al., Ann. Neurology, 35, 269 (1994), Ricker et al., Neurology, 44, 1448 (1994)).
DM1 is caused by an expanded CTG repeat on chromosome 19 that is both in the 3′ untranslated region of the dystrophia myolonica-protein kinase (DMPK) gene, and in the promoter region of the immediately adjacent homeodomain gene SIX5 (Groenen and Wieringa, Bioessays, 20, 901 (1998), Tapscott, Science, 289, 1701 (2000)). How the CTG expansion in a noncoding region of a gene causes the complex DM phenotype remains unclear. Suggested mechanisms include: (i) haploinsufficiency of the DMPK protein; (ii) altered expression of neighboring genes, including SIX5; and (iii) pathogenic effects of the CUG expansion in RNA which accumulates as nuclear foci and disrupts cellular function. Several mouse models have developed different aspects of DM1: a model expressing mRNA with CUG repeats manifests myotonia and the myopathic features of DM1; a DMPK knockout has cardiac abnormalities; and SIX5 knockouts have cataracts. Taken together, these data have been interpreted to suggest that each theory may contribute to DM1 pathogenesis and that DM1 may be a regional gene disorder.
To better define the pathophysiological cause of DM, we have studied families with many of the clinical features of DM but without the DM1 CTG expansion. After genetic testing became available for DM1, families with DM2 and Proximal Myotonic Myopathy (PROMM) were identified and linkage analysis excluded involvement of the DM1 locus, as well as excluding the muscle chloride and sodium channel genes. Proximal Myotonic Dystrophy (PDM) and Myotonic Dystrophy type 2 (DM2) were subsequently described, broadening the recognized phenotype of non-DM1 forms of dominantly inherited multisystemic myotonic disorders. In 1998 the DM2 locus was mapped to 3q21, and it was demonstrated that the genetic cause of PROMM map to the same locus in many families.
Defining a second human mutation that causes the multisystemic effects of DM, and identifying what is common to these diseases at the molecular level, provides an independent means of determining the pathogenic pathway of DM and allow methods for diagnosing this disease to be developed.